Improving Biopharmaceutical Properties of Vinpocetine Through Cocrystallization.

Vinpocetine is a poorly water soluble weakly basic drug (pKa = 7.1) used for the treatment of several cerebrovascular and cognitive disorders. Because existing formulations exhibit poor bioavailability and scarce absorption, a dosage form with improved pharmacokinetic properties is highly desirable. Cocrystallization represents a promising approach to generate diverse novel crystal forms and to improve the aqueous solubility and in turn the oral bioavailability. In this article, a novel ionic cocrystal of vinpocetine is described, using boric acid as a coformer, and fully characterized (by means of differential scanning calorimetry, solid-state nuclear magnetic resonance, powder and single-crystal X-ray diffraction, and powder dissolution test). Pharmacokinetic performance was also tested in a human pilot study. This pharmaceutical ionic cocrystal exhibits superior solubilization kinetics and modulates important pharmacokinetic values such as maximum concentration in plasma (Cmax), time to maximum concentration (tmax), and area under the plasma concentration-time curve (AUC) of the poorly soluble vinpocetine and it therefore offers an innovative approach to improve its bioavailability.

A case report of massive acute boric acid poisoning.

Boric acid comes as colourless, odourless white powder and, if ingested, has potential fatal effects including metabolic acidosis, acute renal failure and shock. An 82-year-old male was brought to the emergency room 3 h after unintentional ingestion of a large amount of boric acid. Clinical course was monitored by collecting data at admittance, 12 h after admission, every 24 h for 5 days and again 1 week after admission. During the first 132 h, serum and urinary concentrations of boric acid were measured. Serum boric acid levels decreased from 1800 to 530 microg/ml after haemodialysis and from 530 to 30 microg/ml during the forced diuresis period. During dialysis, boric acid clearance averaged 235 ml/min with an extraction ratio of 70%. The overall patient's condition steadily improved over 84 h after admission. In conclusion, early treatment with forced diuresis and haemodialysis may be considered for boric acid poisoning, even if signs of renal dysfunction are not apparent, to prevent severe renal damage and its complications.

Successful treatment of a rare case of boric acid overdose with hemodialysis.

There is little published experience with the extracorporeal treatment of boric acid overdose, although the pharmacokinetic properties of boric acid suggest a potential role for hemodialysis. We report a rare case of potentially toxic boric acid overdose that was treated successfully with hemodialysis. Based on our experience in this patient and a review of previously reported cases, hemodialysis is effective in decreasing serum boric acid levels and should be considered in the treatment of patients with acute boric acid intoxication.

Usefulness of forced diuresis for acute boric acid poisoning in an adult.

BACKGROUND: Boric acid is generally not recognized as a poisonous substance. However, boric acid has potentially fatal actions such as hypotension, metabolic acidosis and oliguria. Death may result from circulation collapse and shock. OBJECTIVE: We present a clinical case history of the successful use of forced diuresis with furosemide and intravenous fluid for boric acid poisoning. SUBJECT: A 26-year-old female who attempted suicide by consuming a large quantity of boric acid. She was brought to the hospital in a state of clouded consciousness, fever and erythema 14 h after ingestion. METHOD: 3.25 L of intravenous fluid and 100 mg of furosemide were administered over a period of 4 h in the intensive care unit and the serum and urinary concentrations of boric acid measured. RESULTS: The elimination rate of boric acid obtained with diuresis was similar to that obtained with haemodialysis on a previous occasion when the same patient attempted suicide with boric acid. The patient showed only temporary emesis and diarrhoea along with erythema, and was moved to the general ward 4 h after admission. Although in the general ward the patient's fever persisted and nausea, vomiting and headache often recurred, possibly because of an insufficient dose of furosemide, the patient's condition steadily improved over the 64 h after admission. CONCLUSION: Forced diuresis without haemodialysis is recommended early after admission for boric acid poisoning.

A comparative review of the pharmacokinetics of boric acid in rodents and humans.

The pharmacokinetics of boric acid (BA) have been studied in animals and humans. Orally administered BA is readily and completely absorbed in rats, rabbits, and humans, as well as other animal species. In animals and humans, absorbed BA appears to be rapidly distributed throughout the body water via passive diffusion. Following administration of BA, the ratio of blood: soft tissue concentrations of boron (B) is approx 1.0 in rats and humans; in contrast, concentrations of B in bone exceed those in blood by a factor of approx 4 in both rats and humans. In rats, adipose tissue concentrations of B are only 20% of the levels found in blood and soft tissues; however, human data on adipose tissue levels are not available. BA does not appear to be metabolized in either animals or humans owing to the excessive energy required to break the B-O bond. BA has an affinity for cis-hydroxy groups, and it has been hypothesized to elicit its biological activity through this mechanism. The elimination kinetics of BA also appear to be similar for rodents and humans. BA is eliminated unchanged in the urine. The kinetics of elimination were evaluated in human volunteers given BA orally or intravenously; the half-life for elimination was essentially the same (approx 21 h) by either route of exposure. In rats, blood and tissue levels of B reached steady-state after 3-4 d of oral administration of BA; assuming first-order kinetics, a half-life of 14-19 h may be calculated. The lack of metabolism of BA eliminates metabolic clearance as a potential source of interspecies variation. Accordingly, in the absence of differences in metabolic clearance, renal clearance is expected to be the major determinant of interspecies variation in pharmacokinetics. Because glomerular filtration rates are slightly higher in rats than in humans, the slight difference in half-lives may be readily explained. The most sensitive toxicity end point for BA appears to be developmental toxicity in rats, with a No Observed Adverse Effect Level (NOAEL) and Lowest Observed Adverse Effect Level (LOAEL) of 55 and 76 mg BA/kg/d, respectively. Mean blood B levels in pregnant rats on gestation day 20 in the pivotal developmental toxicity study were reported to be 1.27 and 1.53 mcg B/g at the NOAEL and LOAEL, respectively. Blood B concentrations in humans are well below these levels. Average blood B levels in the most heavily exposed worker population at a borate mine was 0.24 mcg B/mL, and the estimated daily occupational exposure was equivalent to 160 mg BA/d. Blood B levels in the general population generally range from 0.03 to 0.09 mcg B/mL. These blood B values indicate an ample margin of safety for humans. In summary, the pharmacokinetics of BA in humans and rodents are remarkably similar, and interspecies differences in pharmacokinetics appear to be minimal.

Developmental effects of boric acid in rats related to maternal blood boron concentrations.

Timed-mated Sprague-Dawley rats (60/group) were exposed to boric acid (BA) from gestational days (gd) 0 to 20. BA added to the diet (0, 0.025, 0.050, 0.075, 0.1, or 0.2%) yielded boron (B) intakes of <0.35 (control), 3, 6, 10, 13, or 25 mg B/kg body wt/d. Approximately one-half of the dams/group were terminated on gd 20, maternal whole blood collected and frozen, and prenatal outcome (fetal growth, viability, and morphology) evaluated. Remaining dams received control diet beginning on gd 20, and litters were monitored throughout lactation. Blood samples were prepared by a high-temperature alkaline ashing method and analyzed for B by inductively coupled plasma (ICP) optical emission spectrometry. On gd 20, blood B concentrations of 1.27 +/- 0.298 and 1.53 +/- 0.546 microg B/g were associated with the no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) (10 and 13 mg B/kg/d, respectively) for developmental toxicity. Developmental toxicity persisted postnatally only at 25 mg B/kg/d, a dose associated with >10-fold increase in maternal blood B (2.82 +/- 0.987 vs. 0.229 +/- 0.143 microg B/g for controls). Maternal blood B concentrations were: 1. Significantly elevated in all BA-exposed groups. 2. Positively correlated with maternal BA intake. 3. Inversely correlated with fetal body weight at doses above the NOAEL.

Selectivity of boron carriers for boron neutron capture therapy: pharmacological studies with borocaptate sodium, L-boronophenylalanine and boric acid in murine tumors.

Borocaptate sodium (BSH) and L-boronophenylalanine (L-BPA) are two boron carriers used for boron neutron capture therapy (BNCT) in the treatment of glioblastoma and melanoma, respectively. The suitability of these two compounds was evaluated on the basis of pharmacokinetic studies aiming at characterizing their biodistribution, tumor uptake and tumor selectivity. Boric acid was also used as a reference compound since it is nonselective and relatively freely diffusible. The compounds were investigated in two tumor models, a B16 pigmented melanoma and the RIF1 sarcoma. Mice were sacrificed after different boron doses at various post-injection times and tissue and plasma levels measured using inductively coupled plasma atomic emission spectroscopy (ICP-AES). The proposed minimum effective tumor boron concentration of 15 ppm was achieved in both tumor models for the three compounds tested, although only for L-BPA in the melanoma was this achieved when tumor-plasma ratios were above 1. In the RIF1 model, maximum tumor concentrations of 44 and 31 ppm B were reached after administration of 50 micrograms B/g body weight for boric acid and BSH, respectively. After administration of 12.5 micrograms B/g of L-BPA, maximum concentrations of 15 and 21 ppm were found in the RIF1 and B16 models, respectively. Tumor-plasma ratios (TPR) for BSH remained close to or below unity at all times studied in both tumors. Brain levels of BSH were very low, however, leading to tumor-brain ratios markedly greater than 1 at all times. L-BPA and boric acid showed TPR values above unity in both tumor models, reaching 3.2 in B16.(ABSTRACT TRUNCATED AT 250 WORDS)

A fatal case of acute boric acid poisoning.

A 77 year-old male mistakenly ingested an estimated 30 g of boric acid as a single oral dose to stop hiccups. On admission, he had vomiting, diarrhea, and hiccups. Laboratory data was diagnostic of acute renal failure. Hemodialysis and charcoal hemoperfusion were performed in series. The serum concentration of boric acid was reduced by the therapy, but the patient died due to cardiac insufficiency. Acute boric acid poisoning resulting from a single oral dose in adults has rarely been reported. Our case is the fourth fatal case in adults since the 1920s following a single, acute ingestion of boric acid.

Tissue disposition of boron in male Fischer rats.

Boric acid (H3BO3), an inorganic acid with widespread commercial use and consumer exposure, impairs fertility in male rodents at dose levels lower than those required to cause other adverse effects. Previous studies found a testicular lesion in adult Fischer rats fed 9000 ppm boric acid (1575 ppm boron) and slightly reduced basal serum testosterone levels. A CNS-mediated hormonal component to this lesion was suggested. Detailed data on the tissue disposition of boron in the rat, including accessory sex organs and the brain, are lacking. This study examined the tissue disposition of boron in reproductive, accessory sex organs, and other selected tissues in adult male Fischer rats fed 9000 ppm boric acid to determine if selective accumulation of boron in reproductive tissues, accessory sex organs, and/or the brain might correlate with and explain the apparent selective testicular toxicity. Adult male Fischer rats were fed 9000 ppm boric acid for up to 7 days. Animals were killed at 1, 2, 3, 4, and 7 days after the start of exposure. Plasma and excised tissues were heat-digested in acid and analyzed for boron by inductively coupled argon plasma emission spectrometry (ICAP). With the exception of adrenal glands, control boron levels in all tissues examined were below 4 micrograms/g. There was a rapid increase in plasma and tissue boron 1 day after the start of exposure (range 2- to 20-fold), with the exception of adipose tissue. With the exception of bone and adipose tissue, all soft tissues examined, including the testis, epididymis, accessory sex organs, hypothalamus, and rest of brain, appeared to reach steady-state boron levels (range 12-30 micrograms/g) by 3-4 days. Bone boron levels continued to increase up to the termination at 7 days (40-50 micrograms/g by Day 7). Bone attained the greatest concentration of boron (2- to 3-fold over plasma levels) while levels in adipose tissue were 20% of plasma levels during the 7-day exposure period. All other tissues appeared to show no appreciable accumulation of boron over plasma levels. The data suggest that neither the apparent selective testicular toxicity nor the slight CNS hormonal effect associated with boric acid exposure can be explained on the basis of selective accumulation of boron in the testis or brain/hypothalamus, respectively. Thus, the testicular toxicity is likely the result of certain biological processes that are unique to the testis and which are targets of boron exposure.

[Determination of boric acid in biological materials by curcuma paper].

The field of legal medicine has seen a recent increase of poisoning by boric acid and, in cases of emergency, a simple method of making a qualitative analysis of the boric acid content is a necessity. Thus, we have examined curcuma paper (turmeric paper) to see if it can provide a qualitative analysis of the boric acid content in biological materials, so as to identify cases of poisoning. It was found that curcuma paper can provide a preliminary analysis of the quantitative content of boric acid, and that about 0.1 mg/ml of boric acid can be determined. The steps for this testing method follow. First, either blood or urine is acidified with a 6 N concentration of hydrochloric acid, i.e., in the case of urine, 0.5 ml of urine is added to 0.1 ml hydrochloric acid, and for blood, 0.5 ml of blood is added to 0.2 ml hydrochloric acid. If the sample is not sufficiently acidic, more hydrochloric acid is added. Next, a drop of the sample is placed on the curcuma paper and, after drying at room temperature, a red stain results if boric acid is present. (Rosocyanin is formed by the reaction of boric acid and protonated curcumin). Then, a 1 N concentration of sodium hydroxide is dropped onto the stained place, and if rosocyanin is present, the stain will turn blue. Informatively, to make curcuma paper, filter paper (No. 2) is soaked in a saturated curcumin/ethanol solution and then air dried.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical manifestations of toxicity in a series of 784 boric acid ingestions.

A retrospective chart review was conducted at two regional poison centers to determine the clinical outcome of boric acid ingestions and to assess the relationship between serum boric acid levels and clinical presentation. A total of 784 cases were studied; all but 2 were acute ingestions. No patients developed severe manifestations of toxicity, and 88.3% were entirely asymptomatic. The most common symptoms were vomiting, abdominal pain, and diarrhea. Lethargy, headache, lightheadedness, and atypical rash were seen less frequently. Boric acid levels were obtained in 51 patients and ranged from 0 to 340 micrograms/mL. Blood levels were 70 micrograms/mL or more in 7 patients; 4 remained asymptomatic, whereas the other 3 had nausea or vomiting. Dialysis was performed in 4 of these 7 patients, only 1 of whom had symptoms (vomiting). On the basis of data from 9 patients, the mean half-life of boric acid was determined to be 13.4 hours (range, 4.0 to 27.8). Hemodialysis in 3 patients significantly shortened the half-life compared with pre- and postdialysis half-lives. Our results suggest that acute boric acid ingestions produce minimal or no toxicity and that aggressive treatment is not necessary in most patients.

Ingestion of boric acid by infants.

Boric acid solution was inadvertantly used to dilute concentrated formula and was fed to 24-day-old and 14-month-old siblings. Total amounts ingested were 2.6 g and 1.95 g, respectively. Symptoms of toxicity included irritability, diarrhea, and perineal erythema (in the younger child only). Peak boric acid levels were 147 micrograms/ml in the 24-day-old and 56 micrograms/ml in the 14-month-old. Peritoneal dialysis was utilized in the younger child, while the older child required only symptomatic care. Serum boric acid half-lives were approximately ten hours (24-day-old) and eight hours. Neither child developed severe toxicity; both were asymptomatic at one-month follow-up.

Seizure disorders and anemia associated with chronic borax intoxication.

During the course of investigation of two infants with seizure disorders it was discovered that both had been given large amounts of a preparation of borax and honey which resulted in chronic borate intoxication. In one child a profound anemia developed as well. The symptoms of chronic borate intoxication are different from those of the acute poisoning with which we are more familiar. The borax and honey preparations are highly dangerous and should no longer be manufactured or distributed for sale.